Primary Diagnosis. Management of small renal tumors continues to change. and now urologists seek to incorporate new and important information as they plan surgery. Interference of excreted [¹⁸F]FDG by the kidneys into the urinary tract accounts for the difficulty in identifying renal cancers that accumulate [¹⁸F]FDG but at levels that do not allow discrimination from normal urinary excretory tissue [31]. Various studies have been performed that have confirmed that [¹⁸F]FDG PET offers little advantage over conventional imaging in the detection of primary renal malignancy [31–36]. As a result of variable sensitivity that ranges from 40% to 94%, [¹⁸F]FDG PET is not used in the detection of primary RCC [31–37]. Kang et al. demonstrated a sensitivity and specificity of 60% and 100% for [¹⁸F]FDG PET for the detection of primary RCC (CT: 92% and 100%) [36]. Aide et al. reported in a prospective study (n  =  53) that [¹⁸F]FDG PET does not offer any advantage over CT for the characterization of renal masses [32]. In the characterization of renal masses, a high rate of false-negative results was observed, leading to a sensitivity, specificity, and accuracy of 47%, 80%, and 51%, respectively, versus 97%, 0%, and 83%, respectively, for CT. However, in this study [¹⁸F]FDG PET appeared to be an efficient tool for the detection of distant metastasis in RCC. [¹⁸F]FDG PET detected all the sites of distant metastasis revealed by CT, as well as eight additional metastatic sites, leading to an accuracy of 94% versus 89% for CT. Although the role of [¹⁸F]FDG PET in the diagnosis of RCC is limited, [¹⁸F]FDG PET/CT may be used in both staging and restaging RCC and especially for the identification of visceral and bone metastases.

Recurrent and Metastatic Disease. Early detection and ­management of metastatic disease has the potential to improve prognosis and quality of life. A meta-analysis found that [¹⁸F]FDG can be useful in restaging and detection of metastatic disease, based on its acceptable sensitivity and specificity [38]. Figure 20.2 illustrates an example of recurrent and metastatic kidney and bladder cancer. Safei et al. performed [¹⁸F]FDG PET for restaging in 36 patients with advanced RCC and suspected recurrence at distant sites [39]. PET correctly classified 21/25 (84%) of the biopsied lesions (sensitivity and specificity: 88% and 75%). In a small retrospective study (n  =  25), Jadvar et al. reported a sensitivity of 71%, specificity of 75%, accuracy of 72%, negative predictive value of 33%, and positive predictive value of 94% for the performance of PET in detection of recurrent and metastatic RCC [40]. Dilhuidy et al. obtained similar results for sensitivity and positive predictive value, i.e., 75% and 92%, respectively [41]. The authors concluded that, when positive, an [¹⁸F]FDG PET scan may modify the decision made. When negative, it should not modify decision making especially for surgery, owing to its low sensitivity. A detailed analysis of sensitivity and specificity of [¹⁸F]FDG PET versus CT was reported by Kang et al. in a study including 66 patients with suspected or known RCC [36]. For retroperitoneal lymph node metastases and/or renal bed recurrence, the sensitivity and specificity for [¹⁸F]FDG PET were 75.0% and 100.0% and for CT 92.6% and 98.1%, respectively. PET had a sensitivity of 75% and a specificity of 97.1% for metastases to the lung as compared to 91.1% and 73.1%, respectively, for chest CT, while PET had a sensitivity of 77.3% and specificity of 100% for bone metastases as compared to 93.8% and 87.2% for combined CT and bone scans. Overall, the specificity of PET was generally higher than that of any other test or a combination of CT and bone scan (for bone lesions). One limitation of the study is that a PET scanner was used and not a combined PET/CT scanner, which is more accurate in staging malignancies.

In a recent large study by Park et al., a hybrid PET/CT scanner and [¹⁸F]FDG was used in the follow-up (mean 24.3 months, range 4–88 months) after surgical treatment of 63 patients with advanced RCC [42]. The [¹⁸F]FDG PET/CT accurately classified the presence of a recurrence or metastasis in 56 (89%) patients. [¹⁸F]FDG PET/CT had an 89.5% sensitivity, 83.3% specificity, 77.3% positive predictive value, 92.6% negative predictive value, and 85.7% accuracy in detecting recurrence or metastasis, which was not significantly different from the results with conventional methods (chest radiography, abdominopelvic CT, and whole body bone scan). The conventional methods had a sensitivity, specificity, PPV, NPV, and accuracy of 94.7%, 80.0%, 75.0%, 96.0%, and 85.7%, respectively. The authors concluded that for the surveillance of high-risk RCC, [¹⁸F]FDG PET/CT had results that were as good as conventional methods. Furthermore, they concluded that [¹⁸F]FDG PET/CT appears to be an effective surveillance tool, with the advantage of coverage of the entire body in one procedure and no risk of renal functional damage or allergy to contrast agents and with good performance.

Assessment of Response to Therapy. Recently, Vercellino et al. evaluated the accuracy of [¹⁸F]FDG PET/CT in assessing early response to sunitinib treatment of 12 patients with metastatic RCC [43]. Patients had an [¹⁸F]FDG PET/CT at baseline and another one for follow-up at the end of the first cycle (at day 42). For each examination, all lesions were registered and the maximum standardized uptake value (SUVmax) was measured. The metabolic response on PET was assessed (using European Organization for Research and Treatment of Cancer criteria), and morphologic response on CT at day 84 after two cycles (using Response Evaluation Criteria in Solid Tumors) was used as the reference standard. Early PET/CT findings, after one cycle of sunitinib, were consistent with later CT results in 9 patients of 11 assessable patients: 1 patient progressed on PET and CT, 7 patients had stable disease, and 1 had a partial response. The other 2 patients had a metabolic partial response on PET and stable disease on CT. However, one of these patients achieved a partial response later in follow-up. The results indicate that [¹⁸F]FDG PET/CT may be used for the early evaluation of response to sunitinib in metastatic RCC. However, larger studies are needed to evaluate the role of [¹⁸F]FDG PET/CT in the assessment of response to sunitinib treatment.

New radiotracers based upon compounds that are selectively accumulated by RCC or radiopharmaceuticals, which are not excreted in the urine, may be useful for imaging of RCC. Thus, other PET tracers than [¹⁸F]FDG have been used in RCC in the past. The potential of [¹¹C]acetate as a metabolic tracer for RCC has been investigated in three small studies [44, 45]. Acetate is converted to acetyl coenzyme A in the mitochondria, followed by rapid clearance as carbon dioxide through the citric acid cycle. In a study including 18 patients with RCC, Shreve et al. reported increased uptake of [¹¹C]acetate in renal malignancies, with no significant urinary excretion into the urinary tract [45]. In a recent study, Oyama et al. reported similar results [44]. In this study, 20 patients with suspected renal tumors were included, one of whom had 3 lesions. The [¹¹C]acetate PET results were compared to CT and histology from surgery. In 18 patients (18/20), 20 tumors were diagnosed as RCC. Of the 20 RCC, 14 (70%) showed positive PET findings, and 6 were negative. The authors concluded that [¹¹C]acetate is a possible tracer of RCC. In contrast, Kotzerke et al. reported that in 18 patients with suspected renal tumors, the [¹¹C]acetate accumulation in most kidney tumors was not higher than in normal kidney parenchyma [46]. In the study, 21 patients underwent [¹¹C]acetate PET. Tumor localization was known from CT/MRI. Histology was available in 18/21 patients. The results in these 18 patients were reported. Thus, the results on [¹¹C]acetate are conflicting and larger prospective studies are needed to clarify the role of [¹¹C]acetate PET/CT in RCC.

Recently, radiolabeled nitromidazoles, ¹⁸F-fluoromisoni­dazole (¹⁸F-MISO), have emerged as noninvasive techniques for assessing tumor hypoxia. Nitromidazoles are effective against organisms thriving in hypoxic environments and are being within hypoxic yet metabolically active cells. Thus, ¹⁸F-MISO has been used in a number of malignant tumors, where hypoxia has been identified as a risk factor in the prognosis of the tumors. Because RCC is resistant to radiation and chemotherapy, it behaves like a tumor that contains hypoxic cell populations. Lawrentschuk et al. used ¹⁸F-MISO in 11 patients with RCC and in four patients with other tumors in order to assess regional hypoxia in renal tumors [47]. A trend of increased ¹⁸F-MISO uptake in RCC was demonstrated in RCC tumors as compared to normal tissue. However, although ¹⁸F-MISO scans showed significant uptake in other solid tumors, there was only mild ¹⁸F-MISO uptake in the present RCC.

Another new tracer in RCC, ¹⁸F-fluorothymidine (¹⁸F-FLT), which is a radiopharmaceutical based on the nucleic acid thymidine and is able to measure cellular proliferation, has been used in a single case report with a difficult case of renal TCC in a long-standing cyst [48]. Recently, Wong et al. evaluated the uptake of ¹⁸F-FLT in RCC (n  =  27 patients) and compared to [¹⁸F]FDG uptake and immunohistochemical analysis of cellular proliferation (Ki-67) [49]. All 27 patients had preoperative [¹⁸F]FDG and ¹⁸F-FLT PET scans. A strong correlation was found between both ¹⁸F-FLT and [¹⁸F]FDG uptake in RCC and Ki-67 on histopathology. The mean SUVmax for ¹⁸F-FLT and [¹⁸F]FDG in tumors were 2.53 and 2.60, respectively. The results indicate that ¹⁸F-FLT may allow for prediction of more aggressive phenotypes of RCC. However, larger studies are needed to evaluate the role of ¹⁸F-FLT in RCC.

Immuno-PET involves radiolabeling of monoclonal antibodies (mAbs) with positron emitters that bind to an antigen on tumor cells. In recent years, much focus has been on the antibody cG250, which reacts against carbonic anhydrase IX (CAIX). CAIX is overexpressed in clear cell RCC, and the G250 antigen is expressed on the cell surface of more than 90% of clear cell RCC and is not expressed in normal kidney [50–53]. CAIX is involved in cellular pH regulation and has been implicated in some pathogenic processes including tumor progression and is thought to play a role in regulating cell proliferation in response to hypoxic condition [54]. High CAIX expression has been demonstrated in malignancies (renal, ovarian, colorectal, lung, brain, and bladder cancers). CAIX is associated with hypoxia and appears to be a marker of poor prognosis [55]. CAIX expression is regulated by the hypoxia-inducible factor 1α (HIF-1α). Mutation of the VHL genes leads to accumulation of HIF-1α and activation of downstream targets including CAIX [56]. Now CAIX is the best and most powerful diagnostic and predictive marker of clear cell RCC [52, 55].

The half-life of common PET tracers, ¹¹C (20.4 min) and ¹⁸F (109.7 min), is in general too short for use with mAB in vivo. Positron emitters with longer half-lives, like ¹²⁴I (4.2 days), are better suited to the slow pharmacokinetics of radiolabeled mAbs. The optimum uptake of such antibody conjugates in tumors is normally several days for intact immunoglobulins [57]. Recently, ¹²⁴I-labeled antibody chimeric G250 (cG250) has been used to evaluate primary RCC. Divgi et al. assessed whether ¹²⁴I-cG250 PET could predict clear cell RCC in 26 patients with renal masses who were scheduled to undergo surgical resection by laparotomy [58]. ¹²⁴I-cG250 PET accurately identified 15 of 16 clear cell RCC, and all nine non-clear-cell renal masses were negative for the tracer (Fig. 20.3). The sensitivity of ¹²⁴I-cG250 PET for clear cell RCC in this pilot trial was 94% (95% CI 70–100%). The negative predictive value was 90% (55–100%), and specificity and positive predictive accuracy were both 100% (66–100% and 78–100%, respectively). ¹²⁴I-cG250 PET shows promising results in distinguishing clear cell RCC from other subtypes. Preoperative identification of tumor type could have important implications for the choice of treatment for renal cancers. Thus, ¹²⁴I-cG250 PET may be a useful diagnostic imaging tool in the clinical management of renal masses. Imaging with ¹²⁴I-cG250 PET has the potential to change clinical management, in patients where a conservative approach (renal impairment, comorbid disease) may be appropriate in G250 negative tumors. These patients may be selected for nephron-sparing surgery or observed. It has been proposed that a ¹²⁴I-cG250 PET scan may be useful as an alternative to biopsy. However, this has to be evaluated further in larger clinical trials.

Bladder cancer is the most common cancer of the urinary system and is the fourth most common malignancy in men, following prostate, lung, and colon cancer [6]. Bladder cancer incidence is increasing. However, the mortality rate has somewhat stabilized. Incidence peaks in the sixth and seventh decades of life, although a trend toward presentation at younger ages has been suggested [70]. Because of long-term survival and the need for lifelong routine monitoring and treatment, the cost per patient of bladder cancer from diagnosis to death is the highest of all cancers in USA [71]. Rates in males are three to four times those in females [72]. Incidence rates are high in many southern and eastern European countries, in parts of Africa and the Middle East, and in North America [72]. TCC accounts for over 90% of cases and is by far the most common epithelial tumor of the bladder [73]. The second most common cell type is squamous cell cancer (5%), and less than 2% are adenocarcinomas [70]. Several causative risk factors are associated with urothelial tumors. Of these, smoking is one of the most important factors and is consistently associated with the development of TCC. Cigarette smoking increases bladder cancer risk two- to fourfold, and 30–50% of all bladder cancer is caused by cigarette smoking [74]. The latency period is approximately 20–30 years. Painless microscopic or gross hematuria is the initial symptom in over 80% of the patients with urothelial cancer of the bladder, which is why TCC needs to be excluded in patients presenting with these ­symptoms [74].

The standard method of diagnosing bladder cancer continues to be based on direct visualization of the bladder with cystoscopy and subsequent biopsy/resection [75, 76]. In an effort to improve the sensitivity of bladder cancer diagnosis, fluorescence cystoscopy continues to evolve. Several prospective randomized clinical trials have demonstrated increased detection of bladder tumors, particularly Ta tumors and carcinoma in situ (CIS) when using fluorescence cystoscopy [77 78]. One of the distinguishing features of TCC is that it has the highest recurrence rate for any cancer, thereby making rigorous posttherapeutic surveillance, often referred to as “urothelial surveillance,” necessary in all patients [79]. These tumors are also commonly multifocal. They involve any part of the urothelium in a seemingly random manner. Biomarkers: Despite the development of several commercially available urinary markers for diagnosis and surveillance of bladder ­cancer, urinary cytology continues to play an important role in the diagnosis and surveillance of bladder cancer [80]. The specificity of cytology approaches 100%, whereas other markers generally outperform cytology with respect to sensitivity, especially for low-grade disease [75].

Most bladder cancers are “non-muscle invasive” at the time of initial diagnosis. Roughly 70% of newly diagnosed bladder cancer is superficial disease [74]. They are either confined to the mucosa (stage Ta, CIS) or invade the lamina propria but not the muscularis propria (stage T1). Among the superficial cancer group, approximately 70% presents as Ta lesions, 20% as T1, and 10% as CIS [74]. Stage Ta tumors, especially those which are low grade, have a low risk of progression over time, and there is a trend toward more conservative management of these tumors. Therefore, in the majority of these patients, management can be limited to resection and subsequent observation [81]. Stage T1 tumors represent greater challenge to the urologist. Although these tumors are grouped into the category of “superficial,” their risk of progression is much higher over time. The heterogeneity of T1 disease complicates its treatment. It remains a challenge to determine which patient is at high risk of progression versus the patients who will do well with adjuvant intravesical therapy. The European Association of Urology (EAU) and American Urological Association (AUA) have similar recommendations for induction and maintenance treatment in patients based on clinical and pathologic risk factors [81, 82]. Low-risk patients (low-grade Ta) can be monitored on surveillance protocols. Conversely, those patients with high-risk superficial disease (CIS, T1, high-grade Ta, multiple tumors, and >  3-cm tumors) should strongly be considered for adjuvant intravesical therapy. The most widely used agents include the immunotherapy drugs Bacillus Calmette-Guérin (BCG), interferon alpha (IFN-α), and the chemotherapy agent mitomycin C (MMC), among others [82]. BCG represents the only agent known to reduce progression into muscle-invasive bladder cancer [82]. BCG has proven superiority over intravesical chemotherapy with respect to CIS but not for papillary tumors alone [76, 83]. Despite the efficacy of BCG, a substantial number of patients recur or progress. Thus, several studies have used novel agents as well as combination therapy utilizing BCG as a component in an attempt to delay tumor recurrence/progression yielding mixed results [75, 76].

The primary modality for treatment of clinically localized muscle-invasive bladder cancer is surgery, and developments in this field focus on minimizing the morbidity of surgery. Radical cystoprostatectomy with bilateral pelvic lymphadenectomy remains the gold standard for management of muscle-invasive bladder cancer [75, 76]. However, the precise limits of that lymph node dissection are debated [75]. Data from a large group of patients support the aggressive surgical management of invasive bladder cancer [84]. Long-term disease-free survival of up to 70% can be achieved in most patients with organ-confined disease [75, 84]. Bladder preservation strategies (TUR, chemotherapy and radiation therapy, individually or in combination) are sometimes used instead of cystectomy to limit treatment-associated morbidity especially in patients who are unwilling or not medically suited to undergo radical surgery. Neoadjuvant and adjuvant chemotherapy have been utilized in an attempt to improve outcomes for patients with high-risk muscle-invasive disease. Systematic chemotherapy using multidrug regimens is the standard therapy for metastatic disease, and the classic combination is the four-drug regimen MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) [76, 85, 86].